Before a pharmaceutical product exerts its pharmacological effects, the active ingredient (drug) in an oral solid pharmaceutical preparation is released from the preparation in the digestive tract, dissolved in humoral fluid and absorbed into circulating blood. Poorly soluble drugs, however, may fail to satisfactorily exhibit the pharmacological effects because they, because of low solubility, are sometimes excreted out of the body before they are completely dissolved. To date various methods have been investigated for improving the solubility of poorly soluble drugs. For example, a poorly soluble drug is co-milled with a .beta.-1,4-glucan powder (Japanese Patent Examined Publication No. 53-22138), a poorly soluble drug is kneaded with a water-soluble polymeric base material (Japanese Patent Laid-Open No. 61-63614) and a poorly soluble drug is adsorbed to and carried by the surface of processed starch (Japanese Patent Laid-Open No. 63-101333).
It has long been known that the absorbability of orally administered poorly soluble drugs, in particular, depends on particle size. In such oral preparations, the active ingredient is released after disintegration of the tablet, coating or capsule, and the smaller the particle of the active ingredient is, the more rapidly the active ingredient can be dissolved and absorbed in the digestive tract after administration. Therefore, it is a common practice to make poorly soluble drugs as fine as possible by pulverizing, etc. To produce such a finely milled active ingredient, however, it is necessary to use a special pulverizing device or to dry the active ingredient after precipitating it in a particularly fine form from a solvent in a special process, where the wetting agent is often used in large excess.
On the other hand, an excessively fine powder has a drawback of being difficult in handling upon preparation, filling and packing because it shows poor fluidity and flying. It is therefore impossible to feed the powder alone into capsules; usually, capsule-filling of the powder is facilitated by adding a fluidizing agent as a secondary ingredient. This can greatly reduce the content of an active ingredient and necessitate relatively high-dose administration because of poor solubility and poor absorbability. In the case of drugs to be given at high doses such as antibiotics, it is required to increase capsule size or to take some capsules at one time, causing inconveniences to the patients upon usage. After finely powdering, pharmaceutical formulation designing by granulation, tableting, etc. is usually conducted. Such process, however, often requires additives to obtain such properties as disintegration of the preparation, and dissolution, dispersion and absorption of the drug, which, in case of drugs requiring high dose administration, can often cause inconveniences to the patients upon usage for the same reason as above.
It is, therefore, desired that the microgranulated pharmaceutical preparations be made with maintaining the content of the active ingredient as high as possible in order to make the above-described properties such as fluidity and flying optimal without sacrificing the advantages of finely powdering such as improvements in solubility and absorbability. However, the attempt to achieve microgranulation only by granulation technology has limits such as a non-uniform particle size distribution. For example, granulation following finely powdering may be achieved by a large number of conventional granulation technologies such as dry coating granulation using a high speed rotary mixer or another apparatus, solid dispersion granulation, fluidized dry granulation, spray drying granulation and wet granulation. However, all these methods provide granulated particles mostly having particle size of not less than 0.2 mm like granules and fine granules. It is technically difficult to prepare a microgranulated particle having particle size of not more than 0.2 mm from a fine powder at high precision and high productivity. Although there are some reports on the obtainment of not more than 0.2 mm fine particles by spray drying granulation or coating on fine core particles, it has not yet been accomplished to obtain a microgranulated particle from a fine powder at high precision only by granulation technology.
As stated above, microgranulation following finely powdering is useful in increasing the rate of absorption of a drug to be given at a high dose. It is expected that the effects of the present art extends beyond the pharmaceutical field because the microgranulation giving particle size of not more than 0.2 mm can be applied also to food and fertilizers.